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Clinical Presentation & Diagnosis of Extrapulmonary Tuberculosis
Christopher Spitters, MD, MPH
PHSKC Tuberculosis Clinic
CITC Tuberculosis Intensive @ Seattle
June 27, 2019
Disclosures
• Financial ties: none
• Off-label uses: NAAT on extrapulmonary specimens
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Sites of Involvement
Source: http://anatomyid.com/diagrams-for-tuberculosis/diagrams-for-tuberculosis-fileextrapulmonary-tuberculosis-symptoms-svg-wikimedia-commons/ (accessed 06 May 2018).
LungsLymph NodesPleuraPeritoneumBonesBrainLiver/SpleenUrinary tractGenitalsEyesSkin
Pulmonary (68%)
Extrapulmonary (22%)
Both (10%)
Pleural (16%)
Lymphatic (40%)
Bone/joint (10%) Genitourinary (5%
Meningeal (6%)
Other (18%)
Clinical Presentation: Site of Disease
CDC Reported TB Cases by Form of Disease United States, 2015
Peritoneal (5%)
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Pulmonary Involvement in EPTB
• 72 EPTB cases, 2003-2004
• CXR abnormal: 35 (49%)
• Sputum collected (spont-or-induced): 57 (79%)
– AFB smear positive: 5 (9%)
– AFB culture positive: 12 (21%)
– CXR abnormal-vs-normal: 23% vs 19%
– HIV negative, CXR normal: 2/24 culture positive
• Sputum examinations in EPTB patients…may identify potentially infectious cases of TB
Parimon, et al. Chest 2008;134:589-594
Learning Objectives
• List at least 4 extrapulmonary manifestations of TB and potential approaches to confirm the diagnosis in order to promptly diagnose patient with EPTB.
• Explain the need to evaluate patients with extrapulmonary tuberculosis for potential active pulmonary tuberculosis to determine associated risk of transmission.
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EPTB Key Issues
• Diagnosis of pulmonary vs EPTB
• Extension of therapy for certain sites of disease
• Paradoxical worsening & IRIS
• Adjuvant treatment with corticosteroids
• Monitoring response to therapy
Issue Pulmonary Extrapulmonary
Bacillary load Often high Usually low
Imaging Plain radiographyChest CT
CT MRI
Diagnostic specimens
SputumInduce sputumBALPost bronchoscopyGastric aspirate
FNABx: core/needle, excisional/surgicalSerous cavity fluidsJoint fluidsCSF
Sampling Usually multiple Usually single
Tests AFB smear/cultureNucleic acid amplification
AFB smear/cultureNAATCytology/histopathologyCell count & diffProtein (+/- LDH), glucoseADA, gamma-interferon
Smear/culture pos Smear+: 50-70% Culture+:90% Smear+: 25-50%; Culture+:60-70%
Treatment duration 6-9 months usually Bone & joint: 6-9 monthsBrain: 9-12 monthsOthers: 6 months
Corticosteroids No MeningitisSome pericarditis
IRIS/paradoxical worsening
Rare Not uncommon
Response Mycobacteriology, clinical, imaging Clinical, imaging
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Issue Pulmonary Extrapulmonary
Bacillary load Often high Usually low
Imaging Plain radiographyChest CT
CT MRI
Diagnostic specimens
SputumInduce sputumBALPost bronchoscopyGastric aspirate
FNABx: core/needle, excisional/surgicalSerous cavity fluidsJoint fluidsCSF
Sampling Usually multiple Usually single
Tests AFB smear/cultureNucleic acid amplification
AFB smear/cultureNAATCytology/histopathologyCell count & diffProtein (+/- LDH), glucoseADA, gamma-interferon
Smear/culture pos Smear+: 50-70% Culture+:90% Smear+: 25-50%; Culture+:60-70%
Treatment duration 6-9 months usually Bone & joint: 6-9 monthsBrain: 9-12 monthsOthers: 6 months
Corticosteroids Severe respiratory failure MeningitisSome pericarditis
IRIS/paradoxical worsening
Rare Not uncommon
Response Mycobacteriology, clinical, imaging Clinical, imaging
ATS/IDSA/CDC 2017 Dx Guidelines“At present, NAAT testing on specimens other than sputumis an off-label use of the test.”
Issue Pulmonary Extrapulmonary
Bacillary load Often high Usually low
Imaging Plain radiographyChest CT
CT MRI
Diagnostic specimens
SputumInduce sputumBALPost bronchoscopyGastric aspirate
FNABx: core/needle, excisional/surgicalSerous cavity fluidsJoint fluidsCSF
Sampling Usually multiple Usually single
Tests AFB smear/cultureNucleic acid amplification
AFB smear/cultureNAATCytology/histopathologyCell count & diffProtein (+/- LDH), glucoseADA, gamma-interferon
Smear/culture pos Smear+: 50-70% Culture+:90% Smear+: 25-50%; Culture+:60-70%
Treatment duration 6-9 months usually Bone & joint: 6-9 monthsBrain: 9-12 monthsOthers: 6 months
Corticosteroids No MeningitisSome pericarditis
IRIS/paradoxical worsening
Rare Not uncommon
Response Mycobacteriology, clinical, imaging Clinical, imaging
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Radiographic Findings EPTB
• Lympadenopathy with central attenuation, septation (neck, chest, abdomen, pelvis)
• Effusions
• Diskitis osteomyelitis +/- paraspinous abscess
• Enhancement of meninges, peritoneum, pericardium
• Ring enhancing CNS lesions
• Omental stranding, mesenteric adenopathy
• Bowel wall thickening +/- abscess
• Urinary collecting system obstruction +/- renal parenchymal destruction
• Adnexal mass
Typical Findings Extrapulmonary Specimens
• AFB smear: 10-50% sensitive
• AFB culture: 60-90% sensitive
• NAAT 50-75% sensitive
• Necrotizing granulomata
• Protein elevated
– Pleural/peritoneal (>4-5gm/dL)
– CSF (>100-500mg/dL)
• Moderately decreased glucose (~40-50mg/dL)
• Pleocytosis
– Pleural (1,000-5,000 WBC/uL)
– CSF (100-500/uL)
– Lymphocyte predominant differential
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Case A--Presentation
• 23 y/o male from western Africa
• Headache, malaise for several months
• Ptosis, double vision
• Fever x 2 weeks
• No cough, sputum
Case A—Diagnosis (1a)
Meningeal enhancement
Subcortical T2-Flair infarcts
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Case A—Diagnosis (1b)
• CSF – RBC 0
– WBC 357
– Lymphocytes 87%
– Protein 148
– Glucose 56 (vs 130 blood)
– AFB smear neg
– TB PCR neg
• Serum Na 130
• HIV negative
Meningeal enhancement
Subcortical T2-Flair infarcts
Typical Findings CSF in TBM
• Protein elevated: 100-500mg/dL (may be higher in spinal block)
• Moderately decreased glucose (~25-50mg/dL)
• Pleocytosis: 100-500/uL
• Lymphocyte predominant differential, but can be mixed or neutrophilic early in presentation
• TB PCR sensitivity: ~50% (range 40-75%)
• AFB smear sensitivity: ~10% (higher for tisue biopsy and CSF pellicle)
• AFB culture sensitivity: ~50%
• ADA
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Case A—Diagnosis (2)
• Right apical opacity
• Unable to raise sputum
• BAL 2+, PCR+
TBM Clinical Presentation
• Stage I (e.g., headache and fever only)– Non-specific symptoms
– Few or no clinical signs
– AAOx3
• Stage II – Meningismus
– Drowsiness/lethargy
– Focal neurologic deficits
• Stage III– Stupor/coma/seizures
– Gross paresis/paralysis
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Survival in TB-HIV Meningitis by Stage
Török M E et al. Clin Infect Dis. 2011;52:1374-1383
Torok, et al. CID 2011;52:1374
Typical Complications TBM
• Pressure of exudatecranial nerve palsies (e.g., IV, VI, VII), deafness, visual disturbances, other paresis/paralysis
• Hydrocephalus– Communicating (furosemide/acetazolamide)
– Non-communicating (ventriculostomy, shunt)
• Occlusive vasculitis
• SIADH
• Mass effect
• Paradoxical worsening/IRIS
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Corticosteroids in TBM• RCT, double-blinded, age>14, HIV-pos&neg, N=542
• Dexamethasone vs placebo– Month 1: 0.4mg/kg/dx7d0.30.20.1mg/kg/dx7d
– Month 2: 4mg qdx7321mg/kg/dx7d, then off.
• RR death 0.69 (0.52-0.92)
• Severe disability: 18% vs 13% (NS; p=0.27)
• Adv effects: 9% vs 20% (p=0.02)
Thwaites G, et al. NEJM 2004;351:1741-51
• Prevents death• Prevents disability in grade I, but not II or III
Corticosteroids in TBMIn General…Yes
• Generally recommended, especially stage II or III TBM or paradoxical worsening
• Less clear role in tuberculoma or spinal TBM
• Dexamethasone 0.4mg/kg/d split qid or prednisone 1mg/kg/d
• 4 weeks at full dose then 4-week taper ATS/CDC/IDSA 2016 Rx GuidelinesMortality benefitDexamethasone or prednisolone tapered over 6-8 weeks
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Case A—TBM:Treatment
• HRZE + dexamethasone started
• Fully sensitive (sputum); CSF culture neg
• Glucocorticoid-associated DM; insulinmetformin
• Dexamethasone taper @ 8 weeks (6mg qid)
• Recurrent headaches @ 2mg/d
• Dexamethasone back up to 4mg/d then taper (x2)
• Cushingoid
• Finally off dexamethasone at 6 months
• Completed 2HRZE + 10HR DOT
Response to Therapy
ATS/CDC/IDSA 2016 Rx Guidelines:…repeated lumbar punctures should be considered…
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Case B--Presentation
• 23 y/o Vietnamese woman
• R neck swelling, pain
• Otherwise well
• No improvement with amoxicillin/clavulanate
Case B—Diagnosis (1)
• 23 y/o Vietnamese woman
• R neck swelling, pain
• Otherwise well
• No improvement with amox/clav
• CT neck: ~3cm hypodense LN with peripheral enhancement
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Case B—Diagnosis (2)
• 23 y/o Vietnamese woman
• R neck swelling, pain
• Otherwise well
• No improvement with amox/clav
• CXR normal
• CT neck abnormal
• FNA 2+ AFB
• No PCR results
• Bartonella, toxoplasmosis, and EBV seronegative
Case B—Treatment
• 23 y/o Vietnamese woman
• R neck swelling, pain
• CT abnormal; CXR normal
• FNA 2+ AFB
• PCR not done
• Starts HRZE 7/7
• MTB isolated, INH mono-res
• Paradoxical worsening during months 2-3
• Completed 6RZE 7/7
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LN TB: Paradoxical Worsening
• Enlarging, new, or draining LNs
• 20-25% of HIV-negative LN cases
• Median onset: 46 days (IQ: 34-111 days)
• Granulomata, AFB+, culture-negative
• Median duration: 69 days
• Robust response to MTB with treatment and release of antigens
• NSAIDs, corticosteroids, aspiration (none evidence based)
Fontanilla, et al. CID 2011:53(6):555-62.
Case C--Presentation
• 32 y/o Ukrainian male
• L chest pain, dyspnea, fever, fatigue x3wk
• Lost 3 kg
• No cough, sputum
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Case C—Diagnosis (1)
• 32 y/o Ukrainian male
• L chest pain, dyspnea, fever, fatigue x3wk
• Lost 3 kg
• No cough, sputum
• Moderate L effusion
• Compression LLL; otherwise minimal lung abnormalities
Case C—Diagnosis (2)
• 32 y/o Ukrainian male
• L chest pain, dyspnea, fever, fatigue x3wk
• Lost 3 kg
• No cough, sputum
• Moderate L effusion
• 300mL straw-colored fluid
• Protein 5.2gm/dL
• WBC 1200, L 73%, M 14%, P 13%
• AFB smear and TB PCR neg
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Pleural Effusion Evaluation SensitivitySpecimen Cultured AFB Culture Sensitivity
Sputum only 48%
Fluid only 63%
Sputum + Fluid 79%
Ruan SY, et al. Thorax 2012;67:822-7.
Pleural Biopsy• Closed
• Up to 40% of specimens contain no pleural tissue• Image guided gaining favor• Sensitivity (pathology + culture): 80-90%
• Thoracoscopy/VATS: sensitivity approaches 100%
Koegelenberg CF, et al. Respirology 2011;16(5):738-46.Kirsch CM, et al. Chest 1997;112(3):702-6.Vorster, MJ, et al. J Thorac Dis 2015;7(6):981-991
Case C--Pleural TB Rx
• 32 y/o Ukrainian male
• Lymphocytic exudative effusion
• Sputum AFB smr/PCR neg
• Necrotizing granulomata on pleural biopsy; no AFB seen.
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Pleural Fluid ADALow Incidence Setting
•N=338 patients•Lymphocytic exudative •7 pleural TB cases•Typical cut-off: >40•Sensitivity: 85%•Specificity: 90%•PPV: 85%•NPV: 99%
Arnold, et al. Thorax 2014;69:A62 doi:10.1136/thoraxjnl-2014-206260.121
ADA Limitations• False negatives
– Early disease– Advanced age– Smokers
• False positives– Non-TB empyema, parapneumonic effusions– Mesothelioma, lung and hematologic
malignancies– Rheumatologic conditions
Vorster MJ, et al. J Thorac Dis. 2015 Jun; 7(6): 981–991.
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Pleural Fluid IGRA
“We conclude that commercial IGRAs, performed either on whole-blood or pleural fluid samples, have poor diagnostic accuracy in patients suspected to have TPE.”
Aggarawal AN, et al. J Clin Microbiol 2015 Aug;53(8):2451-9.
Case C--Pleural TB Rx
• 32 y/o Ukrainian male
• Lymphocytic exudative effusion
• Sputum AFB smr/PCR neg
• Declines pleural biopsy
• Start HRZE 7/7
• Pleural fluid/tissue AFB cx = MTB
• Fully sensitive
• Sputum AFB cultures negative
• Continues HRZE 7/7 DOT
• Plan: 2HRZE 7/7 +4HR 3/7 DOT
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Other Serous Compartment TBPericardial Peritoneal
Symptoms Chest painDyspneaNarrowed pulse pressure
Abdominal pain, distension, anorexia
Radiography Enlarged cardiac shadowEffusion (US/CT)
Ascites, fat stranding, adenopathy, studding
SpecimensPCR, AFB smr/cx, cell count/diff, chemistry, ADA, IGRA
Pericardiocentes ParacentesisPeritoneal biopsy
Regimen Standard Standard
Corticosteroids Sometimes No
Corticosteroids in TB Pericarditis• RCT, 2/3 HIV-pos, N=1400 adults
• 2x2 design: prednisolone, M. indicus pranii immunotherapy, placebo
• Prednisolone 120mg/dx7d906030155mg/d
• No difference in death+tamponade+constrictive pericarditis
– HR 0.95 (0.77-1.81; 24% vs 26%; p=0.66)
• Constrictive pericarditis reduced: 4.4% vs 7.8%; HR 0.56 (0.36-0.87; p=0.04)
• Hospitalization reduced: 21% vs 25%; HR 0.79 (0.63-0.99; p=0.04)
• Cancer increased: 1.8% vs 0.6%; HR3.27 (1.03-13.24)—mostly HIV
• M. indicus: no benefit, similar increased risk of cancer
Mayosi, et al. NEJM 2014;371:1121-30Chaisson, Post. NEJM 2014;371:1155-57ATS/CDC/IDSA 2016 Rx Guidelines
Editorial & Prevailing Guidelines:• Routine use should not be endorsed• Yes if high risk for constriction• Large effusion, high cell counts, early
signs of constriction
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Case D--Presentation
• 36 y/o Filipino male
• Returned from 3 month stay back home about 6 months ago where he was caring for his dying grandfather.
• DM-II
• Gradually increasing mid-back pain for 2-3 months, night sweats; now lower extremity weakness and paraesthesiae
• No cough
Case D—Diagnosis (1)
• 36 y/o Filipino male with DM
• Back pain, fever
• CXR normal
• T12-L1 osteomyelitis-diskitis with spinal cord compression
• No psoas abscess
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Case D—Diagnosis (2)
• 36 y/o Filipino male with DM
• Back pain, fever
• Abnl MRI c/w TB
• Surgical debridement, anterior corpectomy with cage placement, grafting, and posterior fixation
• Necrotizing granulomata w/o AFB
• TB PCR neg
• AFB cx pending
• QFT indeterminate
(low mitogen)
Case D--Spinal TB Rx
• 36 y/o Filipino male with DM
• T12-L1 spinal TB with cord compression
• Surgical debridement with cage and posterior fixation
• Started HRZE+B6
• MTB fully sensitive from surgical bx
• Completed 2HRZE+7HR
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Other Sites of EPTBSite Diagnostics Treatment Comment
Urinary tract Urine AFB cultureUrine PCRBiopsy specimens
Standard Flank pain+feverHematuriaSterile pyuria
Genital tract Biopsy specimens Standard Female>maleTubes, ovariesEpididymis
Liver/spleen LFTs: mild cholestatic profileBiopsy (rare)
Standard Not uncommon in disseminated* TB, especially miliary
Ocular ExamPositive TST/IGRAExclusion of other causesAqueous/vitreous fluid (rare)
“Standard”+/- ophthalmic corticosteroids
Anterior uveitisPan uveitis/choroiditisTB bacilli or hypersensitivityChoroidal nodules
Erythema induratum
Biopsy: panniculitis ?? Hypersensitivity (not disease) Some PCR+No organisms
*disseminated = involvement of two anatomically non-contiguous sites
EPTB Summary
• LN, pleura most common; any site can be affected
• CNS TB can be a medical/surgical emergency
• Look for concurrent pulmonary TB
• Dx: imagingsamplingmycobacteriology+
• Rx: CNS 9-12mos, bone 6-9mos, others 6mos
• Corticosteroids: TBM, ?tuberculoma, ?pericardial
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Radiographic Findings—CNS TB
• Basilar meningeal enhancement
• Hydrocephalus
• Ring enhancing lesions
• Granulomata
• Cerebral infarctions
• Edema and/or mass effect
• EncephalomalaciaSeemingly more useful for diagnosis than grading
clinical severity or predicting outcome
CNS TB Evaluation Components
• MRI brain• Plain CXR (+/- CT CAP)• CSF (+/- brain tissue—rarely needed)• Sputum x3 (AFB smr/cx x3; PCR x 1-2)• HIV
• QFT +/- TST ??
Note: Negative TST or QFT results never exclude active TB and indeterminate or false negative results are common in hospitalized patients.
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Basilar Meningeal Enhancement
Bernaerts A, et al. Eur Radiol (2003) 13:1876–1890
Hydrocephalus
Bernaerts A, et al. Eur Radiol (2003) 13:1876–1890
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Tuberculoma
Bernaerts A, et al. Eur Radiol (2003) 13:1876–1890
Multiple Tuberculomata
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Abscess with Mass Effect
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CSF Characteristics
Characteristic CNS TB HSV-1 Enterovirus
No. Cases 20 39 44
CSF leukocytes per ml, median
201 47 85
CSF protein, mg/dl, median 174 71 60
CSF glucose, mg/dl, median 35 69 67
Emerg Infect Dis 2008;14:1473-5
California Encephalitis Project
All 20 CNS TB cases: culture positive 4/17 (24%) CSF TB PCR positive
c/o Timothy Dellit, MD
CNS Penetration of TB DrugsDrug MIC
(ug/mL)Target serum (ug/mL)
Peak CSF(ug/mL)
CSF:MIC Overall
Isoniazid (H) 0.025-0.05 3-5 3-5 >10:1 Good
Rifampin (R) 0.005-0.20 8-24 0.5 >2:1 Inflamed—goodOtherwise--fair
Pyrazinamide (Z)
12.5 20-40 25-40 >2:1 Good
Ethambutol (E) 1.0 2-6 0.5 <1:1 Inflamed-fairOtherwise-poor
Streptomycin (S)
0.4-10 35-45 1-2 ~1:1 Inflamed-fairOtherwise-poor
Levofloxacin 0.25 8-12 -- 10:1 Good
Moxifloxacin -- 3-5 -- -- “Good”-animals
Ethionamide 0.6-2.5 1-5 1 ~1:1 Good
Cycloserine -- 20-35 10-20 -- Good
Linezolid -- 12-24 -- -- Fair (?)
PAS -- 20-60 -- -- “Poor”
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“Intensified” Anti-CNS TB RxRuslami R, et al. Lancet ID 2013;13:27-35
INH (5mg/kg)
RIFPZA(25mg/kg)
MOX(400 or 800mg)
WEEKSNot to scale
0 2wk
13mg/kgIV
Intervention Standard Rx
EMB(750mg
10mg/kg
26wk
or
8wk
INH (5mg/kg)
RIF (15mg/kg)
PZA(25mg/kg)
LEV(20mg/kg)
MONTHS
0 2 9
Initial Continuation
EMB(20mg/kg)
10mg/kg
“Intensified” Anti-CNS TB Rx-2Heemskerk, et al. NEJM 2016;374:124-134
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“Intensified” Anti-CNS TB Rx-2Heemskerk, et al. NEJM 2016;374:124-134
• N=60 enrolled• RIF AUC increased 3x• MOX 400800 AUC 2x
“Intensified” Anti-CNS TB Rx-2Heemskerk, et al. NEJM 2016;374:124-134
• N = ~800 enrolled• No difference in mortality• No impact on HIV+ or HIV-• Marginally significant
reduced mortality in INH-resistant cases (24% vs 39%; p=0.06)
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Tobin, Ramakrishnan, Thwaites Cell 2010, Cell 2012
LTA4H SNP rs17525495Low Inflammation (CC): Harm from dexHigh Inflammation (TT): Benefit from dex
Dex benefit is LTA4H Genotype dependent
CC TT
Goldilocks Phenomenon
Slide c/o Thomas Hawn, MD, PhD
Pleural TB: pleural fluid analysis (Guidelines)
• NAAT should be measured (conditional recommendation, very low-quality of evidence: NAAT sensitivity 55%)
• ADA levels and free IFN-gamma levels should be measured (conditional recommendation, low-quality of evidence)
– Sensitivity ~70%, specificity ~80%
– Caution: • Neither ADA nor IFN- levels are standardized• Provide only supportive evidence
Slide c/o Masa Narita
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